Selegiline brain

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

Selegiline (Eldepryl ) Blocks MAOB metabolism and presynaptic reuptake of DA in the brain Start with 5 mg in the morning if symptoms continue, add 5 mg at noon 5 mg daily may be as clinically effective as 10 mg daily with fewer side effects... 

The monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut. 

This drug is a selective inhibitor of monoaminooxidase B, which suppresses dopamine-inactivation processes and facilitates an increase of its level in the brain. In treating Parkinsonism, selegiline is usually used in combination with levodopa. The most common synonyms of selegiline are deprenyl, eldepryl, eldopal, and others. 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

Selegiline is an irreversible but relatively selective inhibitor of MAO-B. An oral preparation is currently marketed as a treatment for Parkinson s disease. An oral dose produces meaningful inhibition of MAO-B but not MAO-A. The concept behind the transdermal patch is to preferentially deliver more selegiline to the brain than to the liver such that meaningful inhibition of both MAO-A and MAO-B is achieved in the brain but only MAO-B inhibition is achieved in the liver. The... 

The free phenols that are produced in the brain (when they break off during the reaction with AChE), are related to the drug selegiline (Fig. 12.8), which is a monoamine oxidase B (MAO-B) inhibitor, so that they also exhibit such inhibitory activity. MAO-B inhibitors are helpful in Parkinson s disease, mainly because they cause an increase in the level of dopamine, and are also antidepressants. These compounds are currently under investigation as treatment for Alzheimer s disease complicated by other cognitive deficits. 

The MAO inhibitors can be used in patients who have Parkinson s disease, for two reasons. First, this is a disorder in which depression is common. Secondly, the selective type B inhibitor selegiline was originally thought to benefit patients with parkinsonism, possibly by increasing brain dopamine concentrations (16). 

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